Buttigieg graduated from St. Joseph High School in 2000, where he was President and valedictorian of his senior class. In his senior year at St. Joseph's High School, he was honored by Caroline Kennedy and other members of President Kennedy's family during a May 22, 2000, ceremony at the John F. Kennedy Library for his prize-winning essay for the JFK Profiles in Courage Essay Contest. Buttigieg’s winning essay centered on the integrity and political courage demonstrated by U.S. Congressman Bernie Sanders of Vermont, one of nation's only Independent members of Congress. He was also selected as one of two Indiana delegates to the United States Senate Youth Program.

Before graduating from college, Buttigieg worked as an investigative intern at WMAQ-TV, Chicago's NBC news affiliate. Buttigieg also worked as an intern for Jill Long Thompson's 2002 congressional campaign, and later served as an adviser to her 2008 gubernatorial campaign.

After graduating, from 2004 to 2005 Buttigieg worked in Washington, D.C., as conference Director for former U.S. Secretary of Defense william Cohen's international strategic consulting firm, The Cohen Group. He also spent several months working on Senator John Kerry's 2004 presidential campaign, where he was a policy and research specialist.

After graduating from Oxford, he then worked as a consultant at McKinsey and Company, a management strategy consulting firm, for three years, from 2007 through 2010.

Buttigieg was commissioned as a Naval intelligence officer in the Naval Reserves in 2009, and deployed to Afghanistan in 2013. After a seven-month deployment, Buttigieg returned to South Bend. He remains a lieutenant in the Naval Reserve.

He was the Democratic Party candidate in 2010 for State Treasurer of Indiana. Buttigieg lost to incumbent Richard Mourdock, garnering 37.5% of the vote.

Buttigieg was elected Mayor of South Bend on November 8, 2011, with 74% of the vote and took office on January 1 as the youngest mayor of a U.S. city with at least 100,000 residents.

In 2012, Buttigieg demoted the first African American police chief of South Bend, Darryl Boykins, and fired police communications Director Karen DePaepe, following the revelation of taped telephone conversations between four white South Bend police officers and the spouse of an officer. The tapes were alleged to contain "racist content". Buttigieg elected to settle suits brought by Boykins, DePaepe, and the four officers out of court. The Common Council of South Bend sued the Mayor to release at least some of the tapes; this suit is still pending in state court.

In 2013, Buttigieg's replacement for Boykins as police chief, Ron Teachman, was subject to investigation for allegedly not supporting a fellow police officer during an nearby fight. Local advocates expressed concern that the officer Teachman allegedly failed to assist was African American. After a report by the Indiana State Police on the incident, Buttigieg concluded there was no discipline required of Chief Teachman, a decision that caused the head of the Board of Public Safety, Pat Cottrell, to resign in protest. Cottrell and the officer Chief Teachman allegedly failed to assist, Lt. David Newton, requested that the report be released, which Mayor Buttigieg declined to do.

Buttigieg was named a 2014 Aspen Institute Rodel Fellow. He was named a recipient of the John F. Kennedy New Frontier Fenn Award in 2015.

On June 16, 2015, Buttigieg announced in an essay that he is gay. He is the first openly gay executive in Indiana. On December 28, 2017, Buttigieg announced his engagement to Chasten Glezman.

In 2016, Buttigieg drew national attention for the city's handling of an excessive force and civil rights case involving three South Bend police officers and an innocent African American teen, DeShawn Franklin. Suspected of a crime he did not commit, Franklin's home was entered at night by the officers without a warrant, and he was punched and Tasered during the encounter, but was ultimately not arrested. Buttigieg's administration offered the teen's family $15,000 in settlement. The family rejected this offer, and the case went to trial. A jury found that the officers had violated Franklin's civil rights, and he was awarded $18.

On January 5, 2017, Buttigieg announced his candidacy for Chair of the Democratic National Committee in its 2017 chairmanship election. He "built a national profile as an emerging dark horse in the race for the chairmanship with the backing of former DNC Chairman Howard Dean." Buttigieg "campaigned on the idea that the aging Democratic Party needed to empower its millennial members." He withdrew from the race on the day of the election, in his nomination speech.